Synthesis of 2-aminoindolizines by 1,3-dipolar cycloaddition of pyridinium ylides with electron-deficient ynamides

Article abstract of DOI:10.1021/acs.orglett.5b01205

Electron-deficient ynamides, possessing an ynoate or an ynone moiety, have been successfully involved for the first time in a 1,3-dipolar cycloaddition with stabilized pyridinium ylides. These reactions afford an efficient and general access toward a variety of substituted 2-aminoindolizines which can serve as useful precursors for the synthesis of other more complex nitrogen heterocycles.

Full text of DOI:10.1021/acs.orglett.5b01205

Letter
pubs.acs.org/OrgLett
Synthesis of 2‑Aminoindolizines by 1,3-Dipolar Cycloaddition of
Pyridinium Ylides with Electron-Deficient Ynamides
Julien Brioche, Christophe Meyer,* and Janine Cossy*
Laboratoire de Chimie Organique, Institute of Chemistry, Biology and Innovation (CBI), ESPCI ParisTech, CNRS (UMR8231),
PSL Research University, 10 rue Vauquelin, Paris 75231 Cedex 05, France
S
* Supporting Information
ABSTRACT: Electron-deficient ynamides, possessing an ynoate or an
ynone moiety, have been successfully involved for the first time in a 1,3-
dipolar cycloaddition with stabilized pyridinium ylides. These reactions
afford an efficient and general access toward a variety of substituted
2‑aminoindolizines which can serve as useful precursors for the synthesis of
other more complex nitrogen heterocycles.
ecause of their diverse biological activities,1 their photo-
substituted at C2 by a hydrogen atom or a carbon-containing
2
substituent. 2-Aminoindolizines D constitute an interesting
subclass of heterosubstituted indolizines, encountered in
bioactive compounds or used as scaffolds to access poly-
Bphysical properties, and their use as intermediates in the
synthesis of other nitrogen heterocycles,3 indolizines have
elicited considerable interest from researchers.4−13 The 1,3-
nitrogen-containing heterocycles.12 To access 2-aminoindoli-
zines D by 1,3-dipolar cycloaddition with pyridinium ylides A,
O‑phosphorylated hydroxyketeneimines E, generated by Nef
isonitrile and Perkow reactions, have previously been employed
as partners.13 In this case, aromatization occurs by loss of the
corresponding phosphonic acid (Scheme 1, eq 2). We surmised
that a convenient but yet unexplored alternative way to introduce
a protected amino group at C2 on indolizines would rely on the
use of ynamides F as dipolarophiles. In recent years, ynamides
have been involved in a wide variety of ring-forming reactions
including cycloadditions.14,15 The nitrogen atom of ynamides
can either become part of the newly formed nitrogen heterocycle
or be incorporated as an amino substituent onto the created
carbo- or heterocycles.14
dipolar cycloaddition of pyridinium ylides A7 with alkynes B,
followed by aromatization, affords a convergent and straightfor-
ward access toward functionalized indolizines C. Acetylenedi-
carboxylates, ynoates, and ynones have been traditionally
employed as dipolarophiles8 but other suitable partners include
perfluoroalkynylphosphonates,9 bromoalkynes,10 and some
unactivated terminal alkynes11 (Scheme 1, eq 1). However, all
these latter acetylenic dipolarophiles lead to indolizines
Scheme 1. 1,3-Dipolar Cycloaddition Involving Pyridinium
Ylides As a Route to Indolizines
Herein, we report our results on the development of the 1,3-
dipolar cycloaddition of pyridinium ylides A with electron-
deficient ynamides F, possessing an ynoate or an ynone moiety,
as a general and efficient route toward a variety of substituted
2‑aminoindolizines G (Scheme 1, eq 3).
The first task was to identify a suitable class of ynamides16 that
would undergo 1,3-dipolar cycloaddition with the ylide
generated from pyridinium salt 1a, which was initially selected
as the test substrate (Table 1). In the presence of K2CO3 as the
base (MeCN, 80 °C), no cycloadduct 5 was observed with
phenylethynyl N-sulfonylynamide 2 as partner, and the latter
compound was almost quantitatively recovered (Table 1, entry
1). This result was not surprising considering that the pyridinium
ylide generated from 1a, and ynamide 2 are both nucleophilic
species.17,18 The poor dipolarophilic activity of compound 2 led
us to investigate the reactivity of ynamides possessing an
Received: April 23, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01205
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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Table 1. 1,3-Dipolar Cycloaddition of Pyridinium Ylide
Generated from 1a with Ynamides: Optimization of the
Reaction Conditions
Table 2. 1,3-Dipolar Cycloaddition of Pyridinium Ylides with
Ynamides 4, 8, and 9 Incorporating an Ynoate
time
(h)
temp
yield
a
entry ynamide
base
solvent
(°C) product (%)
1
2
3
4
5
6
7
8
9
2
3
3
3
3
3
3
3
4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K3PO4
DBU
MeCN
MeCN
DMF
DMF
DMF
DMF
DMF
DMF
DMF
5
3
2
2
4
4
4
1
4
80
80
50
50
25
25
25
25
25
5
6
6
6
6
6
6
6
7
0
51
68
50
61
63
46
15
45
b
K2CO3
a
b
Isolated yield. 1a (1.2 equiv) and K2CO3 (2 equiv).
electron-withdrawing substituent on the triple bond. Ynamide 3,
substituted by a carbethoxy group, effectively underwent
cycloaddition with the ylide generated from 1a (2.5 equiv) in
the presence of K2CO3 (MeCN, 80 °C, 3 h) and directly afforded
the desired indolizine 6 in 51% yield (Table 1, entry 2). It is
worth noting that no subsequent oxidative treatment was
required because the initially generated cycloadduct underwent
spontaneous aromatization to provide indolizine 6. Performing
the reaction in DMF at 50 °C significantly improved the yield of
6 (68%) (Table 1, entry 3), but attempts to reduce the quantity
of pyridinium salt 1a (1.2 equiv) led to a less satisfactory result
(50%) (Table 1, entry 4). Interestingly, the cycloaddition could
be conveniently carried out at room temperature, and in this case,
indolizine 6 was isolated in 61% yield (Table 1, entry 5). Among
the other inorganic bases screened, the use of Cs2CO3 led to a
comparable result (63%) (Table 1, entry 6), whereas the yield of
6 decreased slightly (46%) with K3PO4 (Table 1, entry 7).
Inorganic bases led to better results than DBU (Table 1, entry 8),
whose higher solubility in DMF presumably resulted in a too
rapid generation of the unstable ylide from pyridinium salt 1a in
the presence of the moderately reactive partner 3. Thus, K2CO3,
which is classically used to generate ylides from the
corresponding pyridinium salts, was selected as the base for
further studies. Interestingly, ynamide 4 in which the nitrogen
atom is substituted by a Boc group also underwent 1,3-dipolar
cycloaddition and afforded the corresponding indolizine 7 (45%)
(Table 1, entry 9). Although the yield of indolizine 6 (61%), in
which the nitrogen atom at C2 is substituted by a tosyl group, was
higher compared to indolizine 7, the more readily cleaved tert-
butyloxy carbamate (Boc) was selected for studying the scope of
the 1,3-dipolar cycloaddition of electron-deficient ynamides with
pyridinium ylides.16,19
a
b
c
Isolated yield. Reaction time 36 h. Reaction run at 50 °C, 6 h.
which the nitrogen atom is substituted by a benzyl, a
cyclopropylmethyl, or a phenyl group, respectively. The
corresponding 2-aminoindolizines 10−15 were isolated in
moderate to good yields (52−70%) (Table 2, entries 1−6). It
is worth mentioning that the substitution pattern of the
pyridinium salts 1e−g was selected purposely to avoid the
formation of regioisomers. As anticipated, for unsymmetrical
pyridinium salts 1f and 1g, the 1,3-dipolar cycloaddition
occurred at the less substituted carbon of the pyridinium ring
(Table 2, entries 5 and 6).
The ylide generated from isoquinolinium salt 1h was also a
suitable partner for the cycloaddition with ynamides 4 and 9,
which led to the corresponding pyrroloisoquinolines 16 (56%)
and 17 (74%), respectively. Nevertheless, a large excess of the salt
1h (5 equiv) was required in both cases to achieve full conversion
as well as a longer reaction time (36 h) for the formation of 16
The 1,3-dipolar cycloaddition of ynamides incorporating an
ynoate moiety was first explored (Table 2). Pyridinium salts
derived from α-halo alkyl and heteroaryl ketones (1b and 1c,
respectively) or α-halo esters (1c−g) were used as precursors of
the corresponding pyridinium ylides (2.5 equiv) under the
previously optimized conditions [K2CO3 (4 equiv), DMF, rt].
Efficient cycloaddition took place with ynamides 4, 8, and 9 in
B
DOI: 10.1021/acs.orglett.5b01205
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(Table 2, entry 7) or a higher temperature (50 °C) to obtain 17
(Table 2, entry 8).20
The highly functionalized 2-aminoindolizines G, arising from
the 1,3-dipolar cycloaddition of stabilized pyridinium ylides A
with electron-deficient ynamides F invariably contain carbonyl
groups at C1 and C3. However, it is possible to take advantage of
the electron-rich pyrrole nucleus to access 2-aminoindolizines
substituted by alkyl chains at C1 and C3. Thus, reduction of both
ketones in compound 23 with NaBH4 led to the corresponding
diol 28 which underwent double deoxygenation by reduction
with Et3SiH in the presence of TFA (CH2Cl2, rt). This sequence
afforded indolizine 29 (55%) substituted by an ethyl group at C1
and a benzyl group at C3, a compound that would formally result
from the 1,3-dipolar cycloaddition between an unstabilized
pyridinium ylide and an unactivated ynamide which cannot be
achieved under the same conditions (Scheme 2).
The 1,3-dipolar cycloaddition was then investigated with
ynamides incorporating an ynone moiety, which were con-
veniently generated by oxidation of the corresponding ynamides
18−22 possessing a propargylic alcohol and used without further
purification (Table 3).21
Table 3. 1,3-Dipolar Cycloaddition of Pyridinium Ylides with
Ynamides 18′−22′ Incorporating an Ynone (Generated from
Alcohols 18−22)
Scheme 2. Synthesis of a 2-Aminoindolizine 29 with Alkyl
Groups at C1 and C3
To illustrate that functionalized 2-aminoindolizines G can
serve as useful building blocks for the elaboration of more
complex heterocyclic compounds, the synthesis of the
indolizinoquinolinone 31, which incorporates a scaffold of
interest in medicinal chemistry,22 was achieved from cycloadduct
24. The Boc group was easily cleaved (TFA, CH2Cl2), and the
resulting N-phenylheteroarylamine 30 (78%) was engaged in a
copper-catalyzed intramolecular amination23 which enabled the
efficient construction of the quinolone part of the indolizino-
quinolinone 31 (74%) (Scheme 3).
Scheme 3. Synthesis of Indoloquinolizidine 31 by
Intramolecular Copper-Catalyzed Amination
a
DMEDA = MeNH(CH2)2NHMe.
In conclusion, we have demonstrated that the 1,3-dipolar
cycloaddition of stabilized pyridinium ylides with electron-
deficient ynamides, activated by an ester or a ketone, provides a
straightforward and convenient access to highly functionalized
2‑aminoindolizines. These results contribute to expand the
repertoire of the cycloaddition reactions in which ynamides can
be successfully involved to produce heterocycles.
a
Isolated overall yield (two steps from the corresponding ynamido
alcohol).
The 1,3-dipolar cycloaddition of ynamido ketones 18′−22′
with ylides derived from pyridinium salts 1a−1c and 1i delivered
the corresponding indolizines 23−27 in moderate to high overall
yields (45−83%, two steps from ynamido-alcohols 18−22). The
scope is rather broad as a variety of 2-aminoindolizines
incorporating either a methyl ketone (Table 3, entry 1), an aryl
ketone (Table 3, entry 2) or a substituted alkyl ketone (Table 3,
entries 3−5) at C1 can be readily obtained by this sequence.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectral data for all new
compounds. The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b01205.
C
DOI: 10.1021/acs.orglett.5b01205
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Shul’ts, E. E.; Shakirov, M. M.; Tolstikov, G. A. Russ. J. Org. Chem. 2011,
AUTHOR INFORMATION
Corresponding Authors
■
47, 581−588. (e) Georgescu, E.; Caira, M. R.; Georgescu, F.; Drag
̆
hici,
B.; Popa, M. M.; Dumitrascu, F. Synlett 2009, 1795−1799.
*E-mail: christophe.meyer@espci.fr.
*E-mail: janine.cossy@espci.fr.
Notes
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(11) Shang, Y.; Zhang, M.; Yu, S.; Ju, K.; Wang, C.; He, X. Tetrahedron
Lett. 2009, 50, 6981−6984.
The authors declare no competing financial interest.
(12) (a) Kucukdilsi, M.; Opatz, T. Eur. J. Org. Chem. 2014, 5836−5844.
(b) Tverdokhleb, N. M.; Khoroshliov, G. E.; Dotsenko, V. V.
Tetrahedron Lett. 2014, 55, 6593−6595. (c) Costa, M.; Noro, J.; Brito,
ACKNOWLEDGMENTS
Financial support from the ANR (DYNAMITE ANR-2010-
BLAN-704 project) is gratefully acknowledged.
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DOI: 10.1021/acs.orglett.5b01205
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